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Mosaic Chromosomal Alterations in Blood Help Explain Origins of Clonal Hematopoiesis

NEW YORK (GenomeWeb) – A team led by the Broad Institute has investigated contributors to clonal hematopoiesis in the blood of healthy individuals, finding six genetic loci associated with deletions or loss of heterozygosity as well as several mosaic chromosomal alterations that increase the risk of blood cancer.

"The biggest surprise was that several subclasses of clonal expansions are actually strongly influenced by inherited genetic variants," co-first author Po-Ru Loh, a genetics researcher affiliated with Brigham and Women's Hospital and the Broad, said in a statement. "That is, certain DNA mutations that are passed along from parents to children strongly increase the likelihood of clonal expansions later in one's life."

Using genotyping array data and a long-range phasing-based computational approach designed to pick up mosaic mutation events present in one blood cell or fewer for every 100 profiled, the researchers narrowed in on thousands of mosaic chromosomal alterations in the DNA of blood samples from more than 151,000 UK Biobank participants. These alterations provided a look at the processes behind clonal hematopoiesis, in which mutations that arise in the blood go on to expand, they explained.

Along with clues to the genetic variants that tend to correspond with certain mosaic chromosomal alterations, the team was able to start focusing in on some of the risky forms of clonal hematopoiesis that eventually progress to blood cancer. The findings were published online today in Nature.

"These data provide insights into clonal expansion, including mechanisms by which inherited variants at several loci act in cis to generate or propel mosaicism," Loh and his colleagues wrote, noting that the analyses also led to specific mosaic chromosomal alterations "that associate strongly with future hematological malignancies."

Although clonal expansions of somatic mutations often occur in healthy individuals, the team explained, these clonal mosaic events may also represent cancer precursors, boosting an individual's risk of developing a hematological cancer at some point down the line.

To explore the frequency and nature of these mosaic alterations in more detail, the researchers brought together SNP array intensity data for 151,202 individuals previously genotyped for the UK Biobank project. In the process, they tracked down 8,342 mosaic chromosomal alterations, ranging in size from 50 kilobases to nearly 250 megabases, in 7,484 of the participants.

More than 5,900 of the mosaic chromosomal alterations occurred in 5 percent of blood cells or fewer, the team reported. In addition to analyses spelling out the types of alterations involved, their distribution across the genome, and frequency by age, sex, and hematopoietic cell lineage, the group used a chromosome-wide scan to search for germline variants associated with specific mosaic events.

The latter search — together with follow-up analyses on whole-genome sequence data from hundreds of Simons Simplex Collection families — led to four loci containing inherited variants that coincided with mosaic losses or copy number neutral loss-of-heterozygosity events at nearby sites on autosomal chromosomes, along with two chromosome X loci with cis or trans ties to mosaic chromosome X loss events.

"A large fraction of carriers of the inherited alleles subsequently acquire and then clonally amplify the mutations in question," the authors wrote. "The high penetrances imply that mitotic recombination is sufficiently common to predictably unleash latent, inherited opportunities for clonal selection of homozygous cells during the lifespan of an individual, corroborating a recent observation of this phenomenon in skin."

The researchers also highlighted mosaic chromosome 12 trisomy events that occurred in individuals who went on to develop chronic lymphocytic leukemia, based on health outcome data collected from UK Biobank participants over four to nine years of follow up. Still other mosaic chromosomal alterations appeared to ramp up the risk of developing other hematological cancer types down the road. 

"Our findings refine the link between mosaicism and blood cancer risk," Loh said. "While this work is still upstream of clinical translation, it improves our understanding of the biology of clonal hematopoiesis and suggests promising directions for future work."